HYPERCOAGULANT STATES IN MALIGNANT LYMPHOMA

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1 Experimental Oncology 27, , 2005 (September) 179 Exp Oncol , 3, HYPERCOAGULANT STATES IN MALIGNANT LYMPHOMA H. Wada 1, *, T. Sase 2, M. Yamaguchi 2 1 Department of Laboratory Medicine, Mie University School of Medicine, Tsu, Japan 2 Second Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. The incidence of severe complications, such as disseminated intravascular coagulation (DIC) in malignant lymphoma, differs between clinical stages and histological types of the disease, but they occur frequently in stage IV or natural killer (NK) cell lymphoma. Patients with stage IV or NK cell lymphoma exhibit abnormal thrombotic and hemostatic states. One of the mechanisms in DIC might involve elevated cytokine expression by lymphoma cells stimulating the expression of tissue factor (TF) in blood cells or surrounding tissue. During chemotherapy for lymphoma, the white blood cell count was significantly reduced at days 1 and 3, but significantly increased at days 7 and 9. At day 7 of chemotherapy, leukocyte TF mrna levels were significantly increased. Plasma concentrations of granulocyte elastase derived-xdp (GE-XDP) levels correlated with D-dimer levels, suggesting that almost all elevated D-dimer is GE-XDP. C-reactive protein (CRP), GE-XDP and D-dimer were significantly elevated in patients with infection, DIC or acute respiratory distress syndrome (ARDS). Analysis of patients with DIC or ARDS revealed that TF mrna correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes during chemotherapy. Key Words: malignant lymphoma, disseminated intravascular coagulation, thrombotic diseases, tissue factor, chemotherapy, leukocyte, granulocyte elastase derived-xdp (GE-XDP). Several studies of malignant lymphoma have been reported in Europe and Asia [1 5], as the frequency of malignant lymphoma has increased as the population ages. Thrombotic disorders and clinical abnormalities of blood coagulation, including deep vein thrombosis (DVT) [6] and disseminated intravascular coagulation (DIC) [7], are the most frequent complications and the second most common cause of death in patients with malignant diseases such as solid tumors [8, 9], acute promyelocytic leukemia (APL) [10] and malignant lymphoma [11]. In hematopoietic malignancy, a recent study showed that the incidence of malignant lymphoma was higher than that of acute myeloblastic leukemia (AML) [12]. The incidence of DIC in malignant lymphoma is not as high but absolute numbers of patients have increased recently according to a survey by the Japanese Ministry of Health and Welfare (Table 1) [7]. It is recognized that patients with malignant lymphoma are in a hypercoagulable state and frequently have associated thrombotic disorders during the clinical course of the disease [13]. One mechanism of hypercoagulability in malignant diseases is the action of tissue factor (TF), which may be tumor cell-derived [14 16] or may originate from the tumor-associated environment [17]. TF is a transmembrane glycoprotein that plays an essential role in initiation of the TF coagulation pathway. TF serves as the receptor that binds to its essential cofactors, factor VII and Received: June 22, *Correspondence: Fax: wadahide@clin.medic.mie-u.ac.jp Abbreviations used: AML acute myeloblastic leukemia; APL acute promyelocytic leukemia; APTT activated partial thromboplastin time; ARDS acute respiratory distress syndrome; ATRA all-trans retinoic acid; CLL chronic lymphocytic leukemia; CML chronic myelocytic leukemia; CRP C-reactive protein; DIC disseminated intravascular coagulation; DVT deep vein thrombosis; GE-XDP granulocyte elastase derived cross-linked fibrin degradation products; IP interstitial pneumonia; PA plasminogen activator; PAI PA inhibitor; PT prothrombin time; TF tissue factor. activated F VII, leading to thrombin generation and fibrin formation [18]. In malignant disease, TF is presumed to play an important role in coagulation abnormalities, and also in abnormal angiogenesis [19], progression [20] and metastasis [21]. DIC is frequent in patients with malignant tumors such as AML, solid cancers or malignant lymphoma. TF is an essential factor for onset of DIC and plasma TF antigens are markedly elevated in those diseases [22]. However, it has been suggested that the main source of TF differs in each disease. Table 1. Underlying diseases associated with DIC from a report by the Japanese Ministry of Health and Welfare in 1998 [7] DIC Total Frequency Sepsis % NHL % Hepatoma % AML % Lung cancer % Respiratory infections % Liver cirrhosis % APL % Gastric cancer % ALL % APL % Fulminant hepatitis % Sepsis % Breast cancer % AML % Acute lymphoblastic leukemia % Acute myelomonoblastic leukemia % Others % Chronic myelocytic leukemia % Acute monoblastic leukemia % HEMOSTATIC ABNORMALITIES IN LEUKEMIA The highest reported frequency of DIC is in APL and the lowest is in chronic myelocytic leukemia (CML) and chronic lymphocytic leukemia (CLL) (Table 2) [23]. TF antigen and activity in leukemic cell homogenates, especially in APL and AML, were previously reported to be significantly elevated [24, 25]. However, in CML, CLL, acute lymphocytic leukemia (ALL) and non-hodgkin s lymphoma (NHL), TF antigen was not as elevated as in APL. Plasma TF antigen levels were also high in APL but low in CML, ALL and NHL [26]. That is, leukemic cells themselves strongly expressed TF spontaneously. There are several hemostatic factors in

2 180 Experimental Oncology 27, , 2005 (September) leukemia cells, including TF, plasminogen activator (PA), PA inhibitor (PAI) [27], F X activator activity, anticoagulant activity [28], elastase-like activity, trypsin-like activity and chymotrypsin-like activity, suggesting that these factors may affect the hemostatic system (Fig. 1). Among them, only TF and PA were associated with DIC (Table 3). Recently, anexin II [29] has been reported to be expressed in APL and to activate fibrinolysis, like the PA stimulator reported previously [30]. PAI and elastase relate to organ failure or vascular endothelial cell injuries. Table 2. Frequency of DIC in hematopoietic malignancies AML 28% APL 96% Acute myelomonocytic leukemia 50% Acute monocytic leukemia 41% ALL 34% CML blastic crisis 15% CML 0% CML 0% Adult T cell leukemia 30% Total 34% In patients with leukemia, hemostatic abnormalities, bleeding and thrombosis are directly caused by TF, PA or annexin II in leukemic cells, and thrombocytopenia is caused by bone marrow suppression (Fig. 2). Among hemostatic abnormalities in leukemia, both hypercoagulabilities and hyperfibrinolysis exist and a bleeding tendency frequently appears. All-trans retinoic acid (ATRA), which inhibits expression of TF or annexin II in leukemic cells, is a useful treatment for APL. Fig. 2. Mechanism of hemostatic abnormalities in patient with acute leukemia. In hemostatic abnormalities of leukemia, both hypercoagulabilities and hyperfibrinolysis exist and bleeding tendency is frequent. TF tissue factor, PA plasminogen activator Fig. 1. Hemostatic factors in leukemic cell homogenates. a M1-2; b APL; c M4-5 acute myelomonocytic leukemia and acute monocytic leukemia; d CMLbc chronic myelocytic leukemia, blastic crisis; e ALL; f NHL non Hodgkin s lymphoma Table 3. Hemostatic factors in leukemic cells and DIC Hemostatic factor DIC Without DIC TF (u/107 cells) 4.97 ± 7** 1.89 ± 0.26 PA (u/107 cells) 2.35 ± 5* 8 ± 0.22 FX activator activity (u/107 cells) 2.32 ± ± 0.35 Elastase like activity (u/107 cells) 8.3 ± ± 2.6 Chymotrypsin like activity (u/107 cells) 20.4 ± ± 4.6 Trypsin like activity (u/107 cells) 26.8 ± ± 5.9 Data are mean ± SD. *p < 0.05; **p < HEMOSTATIC ABNORMALITIES IN MALIGNANT LYMPHOMA In our recent study [13], the frequency of association with DIC or interstitial pneumonia (IP) in patients with malignant lymphoma was 3.2% or 4.1%, respectively (Table 4). Coagulation markers in malignant lymphoma appeared to deteriorate compared to healthy subjects (Table 5). Activated partial thromboplastin time (APTT) and prothrombin time (PT) were slightly prolonged and plasma levels of FDP were markedly elevated in some patients. Plasma levels of fibrinogen and D-dimer were significantly elevated, suggesting the complications of infection or inflammation with hypercoagulable and fibrinolytic states. Plasma levels of D-dimer are markedly increased in solid tumors [31] and malignant lymphoma [32] and were strongly related to future thrombosis [33]. Leukocyte TF mrna and plasma TF antigen were significantly increased in patients with malignant lymphoma, especially DIC or IP. Our results support an assumption that malignant lymphoma predisposes to DIC. The association of DIC with malignant lymphoma was frequently observed in stage IV disease, however no significant differences in APTT, PT and fibrinogen were observed among the four clinical stages. Leukocyte TF mrna, plasma levels of FDP, D-dimer and TF antigen were significantly elevated in stage IV lymphoma. However, leukocyte TF mrna did not correlate with plasma TF antigen (Table 6). There is considerable evidence that the incidence of thrombotic disorders and DIC is increased in patients with advanced cancer [34], particularly in progressive metastatic cases [35]. The incidence of DIC was especially high in NK cell or Burkitt s lymphoma. The incidence of DIC in malignant

3 Experimental Oncology 27, , 2005 (September) 181 lymphoma was apparently distinct for each clinical stage or histological type. Leukocyte TF mrna was markedly increased in some cases of NK cell lymphoma, whereas no significant differences of plasma TF antigen were detected among the nine groups. Furthermore, leukocyte TF mrna was markedly increased in patients in DIC high risk groups. Leukocyte TF mrna reflected activated leukocyte TF expression and is possibly an important marker for predicting the development and/or prognosis of DIC in patients with malignant lymphoma. Table 4. Incidence of severe complications associated with malignant lymphoma IP/ARDS DIC Patients (n=217) 9 (4.1%) 7 (3.2%) Clinical Stage Stage I 37 1 (2.7%) 1 (2.7%) Stage II 42 3 (7.1%) Stage III 33 1 (3.0%) Stage IV 64 4 (6.2%) 6 (9.4%) unknown 31 Histological Type Diffuse large B cell lymphoma 86 5 (5.8%) 1 (1.2%) Follicular lymphoma 26 MALT lymphoma 19 Hodgkin s lymphoma 12 1 (8.3%) Mantle cell lymphoma 10 Marginal zone B cell lymphoma 8 Adult T cell lymphoma 4 Natural killer cell lymphoma 7 3 (42.9%) Burkitt s lymphoma 7 2 (28.6%) 2 (28.6%) Others 38 1 (2.6%) 1 (2.6%) Table 5. Hemostatic abnormalities encountered in patients with malignant lymphoma Studied index All patients Patients complicated DIC Healthy subjects or IP Number of patients APTT (s) 31.3 ± ± 37.8 a 3 ± 1.4 PT (s) 11.9 ± ± ± Fibrinogen (mg/ml) 338 ± 133 c 388 ± 464c 221 ± 23 FDP (mg/dl) 12.9 ± ± 30.7 a 3.9 ± 1.7 D-dimer (mg/ml) 3.3 ± 4.6 c 5.4 ± 8.9b 0.3 ± 0.2 Number of patients Leukocyte TF mrna ratio 1563 ± 2883 c 3509 ± 4514 a 109 ± 144 Plasma TF antigen (pg/ml) 328 ± 243 b 271 ± 290 a 180 ± 115 Data are mean ± SD. a p < 0.05, b p<0.01, c p < compared with healthy subjects. Table 6. Hemostatic abnormalities according to clinical stage Studied index Stage I Stage II Stage III Stage IV Number of patients APTT (s) 30.9 ± ± ± ± 10.0 e PT (s) 12.1 ± ± ± ± 1.5 Fibrinogen (mg/ml) 357 ± ± ± ± 159 FDP (mg/dl) 3.7 ± ± ± ± 40.7 a,c D-dimer (mg/ml) 1.1 ± ± ± ± 6.2 b,c Number of patients Leukocyte TF mrna ratio 742 ± ± ± ± 3827 a,d,f Plasma TF antigen (pg/ml) 234 ± ± ± ± 223 b,d,f Data are mean ± SD. a p < 0.05 compared with stage I; b p < 0.01 compared with stage I; c p < 0.05 compared with stage II; d p < 0.01 compared with stage II; e p < 0.05 compared with stage III; f p < 0.01 compared with stage III. IP is one of the most lethal complications in malignant lymphoma. Alveolar macrophages and cuboidal epithelial cells have been shown to express TF, and high levels of TF antigen were also found in bronchoalveolar lavage fluid [36]. Intravascular or intra-alveolar fibrin deposition is frequently seen in IP. A strong correlation between coagulation and inflammation has been postulated in IP. Endothelial cells are damaged and leak coagulation factor and inflammatory mediators, leading to fibrin deposition in the alveolar space. The incidence of IP is high, particularly in NK cell and Burkitt s lymphoma. Global coagulation markers were shown to be impaired, and leukocyte TF mrna was higher in patients with IP. These findings suggest an enhanced inflammatory reaction in IP, and TF is suggested to have an important role in fibrosis and abnormal coagulation. Activated leukocytes and increased cytokine levels are considered the main pathogenic cause of IP, which may be the same mechanism of DIC in malignant lymphoma. Characteristic pathological changes, such as diffuse necrosis, granulocytic change and angiocentricity (tumor cell invasion around vessels) are observed in NK cell lymphoma. On immunohistochemical staining of NK cell lymphoma [13], TF and von Willebrand factor (vwf) was strongly positive in vascular endothelial cells of surrounding lymphoma tissue, rather than in tumor cells. In contrast, granulocyte macrophage colonystimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) were detected in tumor cells themselves. On the contrary, in CD8-positive T cell lymphoma, both tumor cells and vascular endothelial cells were negative for TF and GM-CSF. vwf was positive in vascular endothelial cells of tumors but the staining was weak compared to that in NK cell lymphoma. On the other hand, in solid cancers, TF antigen was positive on the tumor cell surface in lung, colon, pancreatic and breast cancer, as detected by immunohistochemical staining [15, 37]. In patients with NK cell lymphoma, leukocyte TF mrna was markedly elevated. In DIC associated with malignant tumors, tumor cells are thought to either spontaneously express TF, or the activated tumor environment (endothelial cell or blood cell) secondarily expresses TF in response to inflammatory mediators [38, 39] (Fig. 3). In terms of clinical findings in NK cell lymphoma, high-grade fever and leukocyte elevation were observed despite small tumor volumes. Furthermore, it is possible that TF expression in the vascular endothelial cells induced a hypercoagulable state that induced local thrombosis and the subsequent diffuse necrosis that was observed on histopathological examination of NK cell lymphoma. TF has a close relationship with hemostatic abnormalities of malignant diseases but the mechanism of hemostatic abnormalities might differ between each disease. INFECTIONS AND HEMOSTATIC ABNORMALITIES Since hemostatic parameters have rarely been examined in these patients during chemotherapy, the relationships between activation of leukocytes, infections and hypercoagulability were examined. The changes of hemostatic parameters in patients with malignant lymphoma were prospectively and continually examined before and during combination chemotherapy to elucidate the mechanisms of the onset of hypercoagulable states such as DIC (Table 7) [40]. Complications such as DIC and ARDS occurred secondary to infections at 5 10 days after chemo-

4 182 Experimental Oncology 27, , 2005 (September) Fig. 3. Mechanism of hemostatic abnormalities in patients with malignant lymphoma. Hemostatic abnormalities were observed in NK cell lymphoma, Stage IV lymphoma and in association with infections. NK cell lymphoma produced cytokines such as GM-CSF and TNF-α, which stimulate vascular endothelial cells and infiltrated leukocytes to express TF. therapy in this study. Treatment with various chemotherapeutic regimens did not influence serum CRP and plasma concentrations of TF Ag, GE-XDP, SF, D-dimer and PAI-I. Treatment resulted initially in a significant leukopenia at days 1 and 3, suggesting a significant increase of the risk of infection after chemotherapy. In contrast, significant leukocytosis was observed at days 7 and 9. Leukocytes can produce TF in response to hypercoagulability [41] and cause organ failure by the production of granulocyte elastase [42]. Both leukocyte counts and leukocyte TF mrna levels significantly increased at day 7 of chemotherapy, suggesting that hypercoagulability caused by TF synthesis develops at 7 days after chemotherapy. The risk of DIC or organ failure due to activated leukocytes may be low during days 1 3 and high from day 7 9 after chemotherapy. In patients with infection, the leukocyte TF mrna levels during chemotherapy were markedly elevated, similar to the findings in previous reports [18] and correlated with plasma D-dimer levels (Table 8). CRP correlated with D-dimer and PAI-1, while GE-XDP correlated with D-dimer. In infection, increased levels of lipopolysaccharide [43] or inflammatory cytokines such as TNF-α [44] or interleukin-1β (IL-1β) [45] may upregulate TF expression in leukocytes or vascular endothelial cells. Leukocyte count, serum CRP, leukocyte TF mrna, and plasma concentrations of GE-XDP and D-dimer were significantly elevated in patients with infection (see Table 8). During chemotherapy, CRP, GE-XDP and D-dimer concentrations were significantly elevated in patients with DIC or ARDS. In an analysis of data of patients with DIC or ARDS, leukocyte TF mrna correlated with D-dimer, GE-XDP correlated with leukocyte count, CRP and D-dimer, and D-dimer correlated with CRP, TF mrna and GE-XDP. Plasma levels of GE-XDP correlated with D-dimer levels, suggesting that most elevated D-dimer is GE-XDP. Since GE-XDP is considered to be a marker of activated leukocytes [46], the elevated D-dimer levels may be due in part to activated leukocytes in malignant lymphoma during chemotherapy. In patients with infection, plasma levels of D-dimer and GE-XDP were significantly increased before elevation of leukocyte TF mrna. The hemostatic system in patients with malignant lymphoma is thought to be activated by recovering leukocytes after chemotherapy. Since GE-XDP concentrations correlated with leukocyte count, increased number of activated leukocytes may cause secondary fibrinolysis independent of plasmin. These findings suggest that, after chemotherapy, leukocytes affect the hemostatic system not only via the TF pathway but also via granulocyte elastase. Almost all DIC in malignant lymphoma, with the exception of NK cell lymphoma, is caused by infections as shown in a rabbit DIC model [47]. The

5 Experimental Oncology 27, , 2005 (September) 183 Table 7. Hemostatic abnormalities in patients with malignant lymphoma before and during chemotherapy [46] Before treatment Day 0 Day 1 Day 3 Day 5 Day 7 Day 9 Day 11 Day 13 WBC (x 10 3 /µl) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ** 2.0* CRP (mg/dl) 0.7 ( ) 0.9 ( ) 0.3 ( ) 0.36 ( ) ( ) 1.5 ( ) 0.4 ( ) ( ) ( ) TF mrnax10-6 TF/ * GAPDH (559 1,386) (270 1,167) ( ) (354 1,407) (268 1,222) (339 2,125) (419 1,436) (312 1,386) (302 1,232) TF Ag (pg/ml) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) * GE-XDP (u/ml) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) SF (µg/ml) ( ) ( ) ( ) (0 2.9) ( ) (0 3.4) (0 2.8) ( ) (0 1.5) D-dimer (µg/ml) 1.5 ( ) 2.1 ( ) 1.6 ( ) 1.6 ( ) 1.8 ( ) 1.53 ( ) 1.4 ( 2.1) 1.8 ( ) 1.5 ( ) PAI-I (ng/ml) ( ) 59.1 ( ) 88.1 ( ) 48.0 ( ) 49.8 ( ( ( ( ( ) ) 107.4) 103.5) 13) WBC-leukocyte count, data was shown as median (25 75 percentile); *p < 0.05 compared to before; **p < 0.05 compared to before Table 8. Hemostatic abnormalities in patients with malignant lymphoma before and during chemotherapy [46] Infection Before treatment Day 0 Day 1 Day 3 Day 5 Day 7 Day 9 Day 11 Day WBC (x ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 10 3 /µl) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 5.6* * 4.9** 2.8** 4.5** 4.6** ( ) ( ) ( ) ( 2.2) ( ) ( ) ( ) ( ) ( ) CRP (mg/dl) ( ) ( ) (0.2 ) ( ) ( ) ( ) ( ) ( ) ( ) ,711* 1, TF mrna (529 1,221) (132 1,167) (171 1,583) (488 2,583) (472 1,470) (670 4,714) (738 2,071) (519 1,950) (312 1,394) x10-6 TF/ GAPDH (442 1,429) (320 1,211) ( ) (250 1,037) (293 1,275) (327 1,281) (366 1,232) ( ) ( ) * 3.9* 3.6* 3.5* 4.7* 4.1 GE-XDP ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) (u/ml) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) (0 2.5) SF (µg/ml) ( ) ( ) (0 3.5) (0 2.3) (0 2.5) (0 2.6) (0 2.1) ( ) (0 1.3) WBC-leukocyte count, data are shown as median (25 75 percentile). *p < 0.05 compared to infection-positive, **p < 0.05 compared to infection-positive. diagnosis of DIC in infection is difficult, as plasma fibrinogen levels are not decreased and D-dimer levels are not greatly elevated in DIC of sepsis. The organ symptom of DIC in malignant lymphoma is considered to be ARDS. Serum CRP, and plasma levels of GE-XDP and D-dimer were significantly elevated in patients with infection, DIC or ARDS. Elevated production of TF or granulocyte elastase due to infection may explain the association with DIC or ARDS. In patients with DIC and ARDS, TF mrna in leukocytes during chemotherapy correlated with D-dimer, and GE-XDP concentrations correlated with leukocyte count, CRP and D-dimer. These findings suggest that inflammatory changes are responsible for the increase in TF mrna synthesis and that activation of leukocytes and granulocyte elastase may elicit a hypercoagulable state and organ failure in patients with malignant lymphoma. ACKNOWLEDGMENTS This work was supported, in part, by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. REFERENCES 1. Herrinton LJ, Goldoft M, Schwartz SM, Weiss NS. The incidence of non-hodgkin s lymphoma and its histologic subtypes in Asian migrants to the United States and their descendants. Cancer Causes Control 1996; 7: Biagi JJ, Seymour JF. Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood 2002; 99: Ko YH, Kim CW, Park CS, Jang HK, Lee SS, Kim SH, Ree HJ, Lee JD, Kim SW, Huh JR. REAL classification of malignant lymphomas in the Republic of Korea: incidence of recently recognized entities and changes in clinicopathologic features. Hematolymphoreticular Study Group of the Korean Society of Pathologists. Revised. European-American Lymphoma. Cancer 1998; 83: Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-hodgkin s lymphomas: distributions of the major subtypes differ by geographic locations. Non- Hodgkin s Lymphoma Classification Project. Ann Oncol 1998; 9: Rudiger T, Weisenburger DD, Anderson JR, Armitage JO, Diebold J, MacLennan KA, Nathwani BN, Ullrich F, Muller- Hermelink HK. Non-Hodgkin s Lymphoma Classification Project: Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the non-hodgkin s lymphoma. Ann Oncol 2002; 13: Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O Fallon WM, Melton LJ III. The epidemiology

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